The worm C. elegans has a particularly active gut that voids its intestinal contents every 50 seconds. Part of this process is mediated by a contraction of posterior muscle cells in response to cues from intestinal cells. Beg et al. screened for mutant animals that did not have proper contractions of the posterior body and identified three genes, pbo-4, pbo-5, and pbo-6, all of which appear to function in a mechanism through which protons act as transmitters (analogous to neurotransmitters, except that they are not released from neurons) that bind to channel proteins on posterior muscle cells to cause contraction. The pbo-4 gene encodes a Na+/H+ exchanger localized to intestinal cells that swaps one Na+ ion into the cell in exchange for an extruded H+ ion. The pbo-5 and pbo-6 genes encode subunits of an ion channel that belongs to a family of proteins that contain a disulfide-bonded loop and are thus known as "Cys-loop" ligand-gated ion channels. Heterologous expression of PBO-5 and PBO-6 in Xenopus oocytes showed that the proteins had channel function that was activated by protons. In the worm, the authors detected rhythmic increases in proton concentrations outside intestinal cells with a green fluorescent protein sensor. Furthermore, release of chemically "caged" protons in the coelomic space between the intestinal cells and muscle induced muscle contraction. Such proton release restored contraction in the pbo-4 mutants (which lack the Na+/H+ exchanger) but did not cause contraction in the mutants lacking components of the channel, which thus appears to act as the proton receptor. Members of another family of acid-sensing ion channels are present in the central nervous system of vertebrates, and deletion of the gene encoding one family member in the mouse causes defects in learning and memory. This leads the authors to speculate that protons may also function as bona fide neurotransmitters in the vertebrate central nervous system. Kim and Zhen provide commentary.